1. Field of the Invention
The present invention relates to the fields of chemistry and biology and more particularly to the field of insecticides. The present invention includes insecticidal carbamates that are useful, for example, for the control of insects, such as mosquitoes, which can be used in applications where exposure to and/or contact with humans is likely. The insecticides of the present invention exhibit species-selective inhibition of acetylcholinesterase (AChE) and are toxic to mosquitoes but not humans.
2. Description of Related Art
Malaria is a global scourge. Over three billion people are at risk of infection by the malaria parasites Plasmodium falciparum and Plasmodium vivax, which cause an estimated one to two million deaths annually. For many in sub-Saharan Africa, especially children, insecticide treated nets (ITNs) provide the only means of defense against Anopheles gambiae, the mosquito vector of the parasites. Carbamate insecticides work by inhibiting acetylcholinesterase (AChE), and are commonly used to control agricultural pests and disease vectors. Human toxicity (resulting from concurrent potent inhibition of human AChE), however, has thus far discouraged deployment of insecticidal carbamates on ITNs. Currently, pyrethroid insecticides have filled this gap. It would thus be desirable to improve current ITN performance by identifying classes of carbamates that possess excellent target selectivity for Anopheles gambaie AChE (AgAChE) over human AChE (hAChE). Such highly selective carbamates would be ideally suited for safe deployment on ITNs, but up to the inventors' work in this area such compounds have been unavailable. The present inventors have identified certain carbamates that are much more potent at AgAChE than at hAChE. This difference in potency for the two species is unanticipated and potentially very useful.
Of carbamates, 3-tert-butylphenyl-N-methyl carbamate (carbamate 1a) has been studied extensively and is known commercially by the name “terbam.” Kolbezen et al. reported that 3-tert-butylphenyl-N-methyl carbamate was a 400 nM inhibitor of Musca domestica (i.e., housefly) AChE (MdAChE) and that it was significantly toxic to houseflies upon topical administration (LD50 50 mg/kg). (Kolbezen, M. J.; Metcalf, R. L.; Fukuto, T. R. Insecticide Structure and Activity, Insecticidal Activity of Carbamate Cholinesterase Inhibitors. J. Agric. Food Chem. 1954, 2, 864-870.) Subsequent studies by Kohn showed carbamate 1a to have similar potency at bovine AChE (530 nM). (Kohn, G. K.; Ospenson, J. N.; Moore, J. E. Carbamate Insecticides, Some Structural Relationships of a Group of Simple Alkyl Phenyl N-Methylcarbamates to Anticholinesterase Activity. J. Agric. Food Chem. 1965, 13, 232-235.) Indeed, in his massive review, Metcalf noted that the few bovine AChE IC50 values reported at that time matched MdAChE IC50 values well. (Metcalf, R. L. Structure-Activity Relationships for Insecticidal Carbamates. Bull. Wld Hlth Org. 1971, 44, 43-78.) The present inventors found that the hAChE IC50 for carbamate 1a (265 nM) is within a factor of 2 of that reported by Kohn for bovine AChE. Thus, previous data tended to support that carbamates, e.g., 3-tert-butylphenyl-N-methyl carbamate (carbamate 1a), that are toxic to houseflies are expected to be toxic to bovine and humans.
To the contrary, however, the present inventors have identified certain carbamates that are much more potent at AgAChE than at MdAChE. This difference in potency for the two insect species is unanticipated and leads to high selectivity for AgAChE relative to hAChE.